Basal cell carcinoma (BCC) is the most common malignancy in the United States;however, it has been relatively understudied in epidemiologic research. Temporal trends indicate that BCC incidence is increasing overall, in young adults, and especially in young women. Data from "early onset" cases support the concept that there are at least two different subgroups accounting for BCCs in individuals below the age of 40?a group with single tumors whose incidence is increasing, presumably due to environmental factors, and a group with multiple tumors whose incidence is stable and who probably have hereditary predisposition to BCCs. The purpose of this study is to assess genetic and environmental risk factors for early onset BCCs and explore the interaction between these factors. This study is an outgrowth of our previous work showing that the PTCH gene underlies both hereditary and sporadic BCCs but applies and extends this work at a population level, with careful consideration of environmental contributions to the disease incidence. Five hundred cases with early onset BCC and 500 controls with benign skin conditions will be recruited from the Yale dermatopathology database for interviews and collection of biological samples. Questionnaire data will be used to assess potential environmental factors that might be related to the increased incidence, especially artificial tanning, excessive solar radiation exposure, smoking, and obesity. The interaction between these environmental variables and genetic variants of MC1R, known to relate to skin cancer susceptibility, will be assessed. Tumors from selected subjects in whom BCC risk appears to be related strongly to a particular environmental exposure will undergo sequencing of the PTCH gene to relate the reported exposure to "signature mutations" in DNA. Subjects with large numbers of BCCs or particularly early age of onset of BCCs will have detailed genetic studies to determine if they have a known hereditary disorder, and if not, to identify novel BCC predisposition genes. Risk factor data are needed to serve as a basis to guide preventive interventions. For example, strong evidence that tanning bed use is an important etiologic factor in early onset BCC, with supporting evidence showing mutational spectra consistent with UVB mutations, could form the basis for stronger legislation to prevent tanning bed use by minors. Alternatively, if smoking or other risk factors are more strongly associated, this suggests a different intervention strategy to reduce the disease. Identification of underlying predisposition genes may help target efforts at prevention to particular genetic subgroups. Thus, this etiologic work is highly and immediately translatable into preventive interventions aimed at reducing the incidence of this exceedingly common malignancy.